The major goal of this project is to identify the gene or genes responsible for inherited predisposition to develop neuroblastoma. Neuroblastoma is a common and often fatal childhood malignancy that arises from primitive neural crest-derived cells and usually occurs sporadically. However, like many other human cancers, some individuals inherit a susceptibility to develop the disease. We hypothesize that predisposition to develop neuroblastoma occurs due to an inactivating mutation in one allele of a tumor suppressor gene. We therefore aim to localize, clone and characterize the familial neuroblastoma predisposition gene. Currently, we have identified 33 families with first or second degree relatives affected by neuroblastic tumors. Specimen collection is ongoing and has been completed on 18 with a total of 133 constitutional samples accrued. We have enhanced the international scope of this project as recent referrals have been made from France and Israel. In the first 2 years of this project we have made significant advances toward the localization of a chromosomal region that contains a predisposition gene. There have been no changes in the overall goals or specific aims of this project and results are too preliminary to site any references. There have been no unanticipated problems nor have we encountered any barriers that would preclude completion of the proposed studies.